Sagar Lonial, MD: Hopefully, down the road as we get more data and additional approvals, we’ll get selinexor approval soon. I think that in my mind partnering with other agents is probably going to be where it’s best utilized. And the reason I say that is partnering with a proteasome inhibitor, both bortezomib and carfilzomib, appears to be particularly active—overcoming drug resistance as well as reducing the incidence of adverse effects. And it really doesn’t make a whole lot of sense to me from a scientific perspective, but combining selinexor with bortezomib appears to reduce the incidence of grade 3 and 4 nausea and diarrhea. So you could almost argue that the best antiemetic for selinexor is a proteasome inhibitor. That’s not typically what we see with combination therapies, and that’s where I think it’s really going to get used more frequently once it’s approved.

Andrzej Jakubowiak, MD, PhD: We achieved not only synergy, the more effective kill of the cells with selinexor, but that can potentially achieve even reversal of lack of response to proteasome inhibitor by adding selinexor to the combination.

The mechanics of that synergy and potentially reversal of refractory status to proteasome inhibitors have been published now, including from our group where we show that there is a very fine mechanism of engaging autophagy as an initial step, and then eventually bringing more enhanced apoptosis, which is self-kill of the cell, when we put those 2 drugs together.

And we have shown in our phase I trial with selinexor, carfilzomib, and dexamethasone, which was a Multiple Myeloma Research Foundation multisite study, presented in a couple of meetings of oral presentations, that indeed we can achieve very good responses, even in patients who have been previously refractory to complex combinations including carfilzomib. For example, more than half of these patients were refractory to combination carfilzomib, pomalidomide and DEX dexamethasone, and they had responded to carfilzomib plus selinexor/dexamethasone combination. And the responses were way over 50%, which you would not have expected actually any. That would be the assumption that the disease is refractory to carfilzomib. So the drug has clearly promise in this regard.

I would predict that this drug, as many other myeloma drugs, will make it’s way to earlier stages of the disease, as it is already being explored; we just don’t have enough data to really discuss it.

Ajai Chari, MD: We’ve had a lot of patients participate on the selinexor STORM study, and we have some patients that are actually still on therapy. So I think the efficacy is definitely there. We’ve seen those results as presented already, the toxicities, as I alluded to. And at the end of the day it’s a risk-benefit management for every drug. And I think if you can optimize the risk-benefit profile for each patient, this is really an important advancement.

That said, we also have to recognize that a drug’s initial approval may not be eventual long-term use. And I think we need to see the single activity. An example would be elotuzumab and panobinostat, which are both drugs that are FDA approved but have limited to no single-agent activity. So even though they’re FDA approved, their use clinically is not as high.

Here we have a drug that is in the heavily treated patient much more so than those drugs. We’re seeing single-agent activity. However, likely long-term use will be in combination. And so Karyopharm Therapeutics has done many studies in combination. We have BOSTON with combination of bortezomib. There’s also an umbrella study that’s looking at combinations with pomalidomide, lenalidomide, with daratumumab. And there’s also an investigator initiated study with carfilzomib. So really selinexor is being partnered with all the available backbone drugs. And each is going to have a slightly different schedule. The IMiDs [immunomodulatory drugs] are likely going to require more dose reduction of selinexor because of the myelosuppression. But hopefully we’ll be able to partner this with the right drug for each patient based on their unique characteristic.

Sagar Lonial, MD: One of the reasons we’ve been able to advance in the field in the last decade or so is that we’ve had new drugs to fall back on whenever patients became resistant to our current standards of care. And in this current situation it’s going to be the proteasome inhibitors, the IMiDs, and now the monoclonal antibodies. So novel agents really represent the next generation of drugs that we have available. And without this, patients who are quad- or penta-refractory will really have no therapeutic options. And fortunately we have lots of options in the clinical trial in the novel agent area.

Ajai Chari, MD: The importance of these agents is we really have no approved strategies for managing these patients. So this signal is really an important one to try to get a handle on these patients. I would add that one of the unmet medical needs in 2018, despite all the drugs that we have approved is the high-risk patient. And so I always emphasize that high-risk patients respond to therapy but they don’t necessarily remain in remission.

And so when we look at all of these drugs, they all improve the outcomes of high-risk patients, but none of them have overcome high risk. And so really we are still on this quest for high-risk. And because selinexor blocks the export of proteins from the nucleolus to the cytoplasm, in particular tumor suppressors such as p53, it’ll be very interesting to see in larger studies whether selinexor is able to overcome high-risk disease more than other drugs. And if so, that may really lend its ability to move into the earlier lines of therapy.

Sagar Lonial, MD: As we think about selinexor, in my own practice we’ve actually had a pretty good experience with this. Patients that really did not have other options came in, and in many cases had very rapid reductions in protein numbers. Almost within the first 2 weeks you can see a reduction in protein.

The dexamethasone is an important adjunct to try and reduce adverse effects as well to enhance efficacy in selinexor, and I think, again, careful attention to management of the GI gastrointestinal] adverse effects can let patients stay on for a longer time, and as they stay on longer they can get more benefit.

Ajai Chari, MD: STORM shows the activity of selinexor and dexamethasone and that may lead to an accelerated approval, but clearly for eventual full approval we need a randomized phase III study, and BOSTON is that study, VD [bortezomib/dexamethasone] plus/minus selinexor. It’s important that in the study design of BOSTON, bortezomib is only given once a week, and dexamethasone as well, and that’s less than the control arm of the bortezomib/DEX twice weekly regimen. So it’s the first phase III study to use that study design of weekly VD. And the reality is that’s what we do in the real world. Very few patients are getting twice weekly bortezomib when given in a triplet setting, and yet study after study gives it twice weekly because of historic reasons.

So this is nice that it’s once weekly and the question will be SVD, or selinexor/ bortezomib/dexamethasone, can it overcome the VD outcomes historically seen. And likely we’ll have less neuropathy given the weekly schedule as well. So I think that’s what’s unique, and we’ll have to see the PFS [progression-free survival] and OS [overall survival] outcomes; of course, eventually OS, but those numbers will likely lead to definitive approval.

Transcript Edited for Clarity

Transcript:

Sagar Lonial, MD: Hopefully, down the road as we get more data and additional approvals, we’ll get selinexor approval soon. I think that in my mind partnering with other agents is probably going to be where it’s best utilized. And the reason I say that is partnering with a proteasome inhibitor, both bortezomib and carfilzomib, appears to be particularly active—overcoming drug resistance as well as reducing the incidence of adverse effects. And it really doesn’t make a whole lot of sense to me from a scientific perspective, but combining selinexor with bortezomib appears to reduce the incidence of grade 3 and 4 nausea and diarrhea. So you could almost argue that the best antiemetic for selinexor is a proteasome inhibitor. That’s not typically what we see with combination therapies, and that’s where I think it’s really going to get used more frequently once it’s approved.

Andrzej Jakubowiak, MD, PhD: We achieved not only synergy, the more effective kill of the cells with selinexor, but that can potentially achieve even reversal of lack of response to proteasome inhibitor by adding selinexor to the combination.

The mechanics of that synergy and potentially reversal of refractory status to proteasome inhibitors have been published now, including from our group where we show that there is a very fine mechanism of engaging autophagy as an initial step, and then eventually bringing more enhanced apoptosis, which is self-kill of the cell, when we put those 2 drugs together.

And we have shown in our phase I trial with selinexor, carfilzomib, and dexamethasone, which was a Multiple Myeloma Research Foundation multisite study, presented in a couple of meetings of oral presentations, that indeed we can achieve very good responses, even in patients who have been previously refractory to complex combinations including carfilzomib. For example, more than half of these patients were refractory to combination carfilzomib, pomalidomide and DEX dexamethasone, and they had responded to carfilzomib plus selinexor/dexamethasone combination. And the responses were way over 50%, which you would not have expected actually any. That would be the assumption that the disease is refractory to carfilzomib. So the drug has clearly promise in this regard.

I would predict that this drug, as many other myeloma drugs, will make it’s way to earlier stages of the disease, as it is already being explored; we just don’t have enough data to really discuss it.

Ajai Chari, MD: We’ve had a lot of patients participate on the selinexor STORM study, and we have some patients that are actually still on therapy. So I think the efficacy is definitely there. We’ve seen those results as presented already, the toxicities, as I alluded to. And at the end of the day it’s a risk-benefit management for every drug. And I think if you can optimize the risk-benefit profile for each patient, this is really an important advancement.

That said, we also have to recognize that a drug’s initial approval may not be eventual long-term use. And I think we need to see the single activity. An example would be elotuzumab and panobinostat, which are both drugs that are FDA approved but have limited to no single-agent activity. So even though they’re FDA approved, their use clinically is not as high.

Here we have a drug that is in the heavily treated patient much more so than those drugs. We’re seeing single-agent activity. However, likely long-term use will be in combination. And so Karyopharm Therapeutics has done many studies in combination. We have BOSTON with combination of bortezomib. There’s also an umbrella study that’s looking at combinations with pomalidomide, lenalidomide, with daratumumab. And there’s also an investigator initiated study with carfilzomib. So really selinexor is being partnered with all the available backbone drugs. And each is going to have a slightly different schedule. The IMiDs [immunomodulatory drugs] are likely going to require more dose reduction of selinexor because of the myelosuppression. But hopefully we’ll be able to partner this with the right drug for each patient based on their unique characteristic.

Sagar Lonial, MD: One of the reasons we’ve been able to advance in the field in the last decade or so is that we’ve had new drugs to fall back on whenever patients became resistant to our current standards of care. And in this current situation it’s going to be the proteasome inhibitors, the IMiDs, and now the monoclonal antibodies. So novel agents really represent the next generation of drugs that we have available. And without this, patients who are quad- or penta-refractory will really have no therapeutic options. And fortunately we have lots of options in the clinical trial in the novel agent area.

Ajai Chari, MD: The importance of these agents is we really have no approved strategies for managing these patients. So this signal is really an important one to try to get a handle on these patients. I would add that one of the unmet medical needs in 2018, despite all the drugs that we have approved is the high-risk patient. And so I always emphasize that high-risk patients respond to therapy but they don’t necessarily remain in remission.

And so when we look at all of these drugs, they all improve the outcomes of high-risk patients, but none of them have overcome high risk. And so really we are still on this quest for high-risk. And because selinexor blocks the export of proteins from the nucleolus to the cytoplasm, in particular tumor suppressors such as p53, it’ll be very interesting to see in larger studies whether selinexor is able to overcome high-risk disease more than other drugs. And if so, that may really lend its ability to move into the earlier lines of therapy.

Sagar Lonial, MD: As we think about selinexor, in my own practice we’ve actually had a pretty good experience with this. Patients that really did not have other options came in, and in many cases had very rapid reductions in protein numbers. Almost within the first 2 weeks you can see a reduction in protein.

The dexamethasone is an important adjunct to try and reduce adverse effects as well to enhance efficacy in selinexor, and I think, again, careful attention to management of the GI gastrointestinal] adverse effects can let patients stay on for a longer time, and as they stay on longer they can get more benefit.

Ajai Chari, MD: STORM shows the activity of selinexor and dexamethasone and that may lead to an accelerated approval, but clearly for eventual full approval we need a randomized phase III study, and BOSTON is that study, VD [bortezomib/dexamethasone] plus/minus selinexor. It’s important that in the study design of BOSTON, bortezomib is only given once a week, and dexamethasone as well, and that’s less than the control arm of the bortezomib/DEX twice weekly regimen. So it’s the first phase III study to use that study design of weekly VD. And the reality is that’s what we do in the real world. Very few patients are getting twice weekly bortezomib when given in a triplet setting, and yet study after study gives it twice weekly because of historic reasons.

So this is nice that it’s once weekly and the question will be SVD, or selinexor/ bortezomib/dexamethasone, can it overcome the VD outcomes historically seen. And likely we’ll have less neuropathy given the weekly schedule as well. So I think that’s what’s unique, and we’ll have to see the PFS [progression-free survival] and OS [overall survival] outcomes; of course, eventually OS, but those numbers will likely lead to definitive approval.